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Evaluation of In Vitro Activity of the Class I PI3K Inhibitor Buparlisib (BKM120) in Pediatric Bone and Soft Tissue Sarcomas.

Anderson JL, Park A, Akiyama R, Tap WD, Denny CT, Federman N - PLoS ONE (2015)

Bottom Line: Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment.Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination.The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Division of Hematology/Oncology, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy. Here, we investigated the in vitro activity of the pan-class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas. Buparlisib inhibited activation of Akt and signaling molecules downstream of mTORC1 (mTOR complex 1) in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines. Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment. Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination. Synergy was observed when buparlisib was combined with the IGF1R inhibitor NVP-AEW541 and the mTORC1 inhibitor rapamycin. The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone. Additionally, the combination of buparlisib with the MEK1/2 inhibitor trametinib resulted in synergy in sarcoma cell lines possessing MAPK pathway mutations. Taken together, these data indicate buparlisib could be a novel therapy for the treatment of pediatric bone and soft tissue sarcomas.

No MeSH data available.


Related in: MedlinePlus

Buparlisib inhibits anchorage independent growth and induces apoptosis.(A) Plot of number and size of ES (TC-174, A4573), OS (KHOS, MNNG), and RMS (RD) colonies formed in soft agar in the presence of DMSO or increasing concentrations of buparlisib. Columns represent the average of three replicates, error bars represent standard deviation. (B) Representative pictures of TC-174 soft agar colonies. (C) Immunoblot analysis of cleaved PARP in ES (TC-174, TC-32, A4573), OS (KHOS), and RMS (RD, SJCRH30) treated with increasing doses of buparlisib for 24 hours. (D) Cell cycle analysis after 24 hours of buparlisib treatment of ES (TC-174, A4573), OS (KHOS), and RMS (RD) cell lines. Data are the mean of two independent experiments.
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pone.0133610.g005: Buparlisib inhibits anchorage independent growth and induces apoptosis.(A) Plot of number and size of ES (TC-174, A4573), OS (KHOS, MNNG), and RMS (RD) colonies formed in soft agar in the presence of DMSO or increasing concentrations of buparlisib. Columns represent the average of three replicates, error bars represent standard deviation. (B) Representative pictures of TC-174 soft agar colonies. (C) Immunoblot analysis of cleaved PARP in ES (TC-174, TC-32, A4573), OS (KHOS), and RMS (RD, SJCRH30) treated with increasing doses of buparlisib for 24 hours. (D) Cell cycle analysis after 24 hours of buparlisib treatment of ES (TC-174, A4573), OS (KHOS), and RMS (RD) cell lines. Data are the mean of two independent experiments.

Mentions: Buparlisib also inhibited cellular proliferation in anchorage-independent growth conditions. Increasing concentrations reduced both soft agar colony number and size (Fig 5A). Cell growth was inhibited within a narrower range than observed for anchorage dependent growth. Minimal effects were observed at concentrations less than 1 μM and no soft agar colony formation occurred at concentrations greater than 2 μM (Fig 5A and 5B).


Evaluation of In Vitro Activity of the Class I PI3K Inhibitor Buparlisib (BKM120) in Pediatric Bone and Soft Tissue Sarcomas.

Anderson JL, Park A, Akiyama R, Tap WD, Denny CT, Federman N - PLoS ONE (2015)

Buparlisib inhibits anchorage independent growth and induces apoptosis.(A) Plot of number and size of ES (TC-174, A4573), OS (KHOS, MNNG), and RMS (RD) colonies formed in soft agar in the presence of DMSO or increasing concentrations of buparlisib. Columns represent the average of three replicates, error bars represent standard deviation. (B) Representative pictures of TC-174 soft agar colonies. (C) Immunoblot analysis of cleaved PARP in ES (TC-174, TC-32, A4573), OS (KHOS), and RMS (RD, SJCRH30) treated with increasing doses of buparlisib for 24 hours. (D) Cell cycle analysis after 24 hours of buparlisib treatment of ES (TC-174, A4573), OS (KHOS), and RMS (RD) cell lines. Data are the mean of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581723&req=5

pone.0133610.g005: Buparlisib inhibits anchorage independent growth and induces apoptosis.(A) Plot of number and size of ES (TC-174, A4573), OS (KHOS, MNNG), and RMS (RD) colonies formed in soft agar in the presence of DMSO or increasing concentrations of buparlisib. Columns represent the average of three replicates, error bars represent standard deviation. (B) Representative pictures of TC-174 soft agar colonies. (C) Immunoblot analysis of cleaved PARP in ES (TC-174, TC-32, A4573), OS (KHOS), and RMS (RD, SJCRH30) treated with increasing doses of buparlisib for 24 hours. (D) Cell cycle analysis after 24 hours of buparlisib treatment of ES (TC-174, A4573), OS (KHOS), and RMS (RD) cell lines. Data are the mean of two independent experiments.
Mentions: Buparlisib also inhibited cellular proliferation in anchorage-independent growth conditions. Increasing concentrations reduced both soft agar colony number and size (Fig 5A). Cell growth was inhibited within a narrower range than observed for anchorage dependent growth. Minimal effects were observed at concentrations less than 1 μM and no soft agar colony formation occurred at concentrations greater than 2 μM (Fig 5A and 5B).

Bottom Line: Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment.Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination.The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Division of Hematology/Oncology, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy. Here, we investigated the in vitro activity of the pan-class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas. Buparlisib inhibited activation of Akt and signaling molecules downstream of mTORC1 (mTOR complex 1) in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines. Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment. Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination. Synergy was observed when buparlisib was combined with the IGF1R inhibitor NVP-AEW541 and the mTORC1 inhibitor rapamycin. The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone. Additionally, the combination of buparlisib with the MEK1/2 inhibitor trametinib resulted in synergy in sarcoma cell lines possessing MAPK pathway mutations. Taken together, these data indicate buparlisib could be a novel therapy for the treatment of pediatric bone and soft tissue sarcomas.

No MeSH data available.


Related in: MedlinePlus